The treatment of Human Immunodeficiency Virus (HIV) infection, known as cause of the acquired immunodeficiency syndrome (AIDS), remains a major medical challenge. HIV is able to evade immunological pressure, to adapt to a variety of cell types and growth conditions, and to develop resistance against currently available drug therapies. The latter include nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), HIV-protease inhibitors (PIs), and the more recent fusion inhibitors.
Although effective in suppressing HIV, each of these drugs, when used alone, is confronted with the emergence of resistant mutants. This led to the introduction of combination therapy of several anti-HIV agents usually having a different activity profile. In particular the introduction of “HAART” (Highly Active Anti-Retroviral Therapy) resulted in a remarkable improvement in anti-HIV therapy, leading to a large reduction in HIV-associated morbity and mortality. Current guidelines for antiretroviral therapy recommend such triple combination therapy regimen even for initial treatment. However, none of the currently available drug therapies is capable of completely eradicating HIV. Even HAART can face the emergence of resistance, often due to non-adherence to and non-persistence with antiretroviral therapy. In these cases HAART can be made effective again by replacing one of its components by one of another class. If applied correctly, treatment with HAART combinations can suppress the virus for many years, up to decades, to a level where the outbreak or progress of AIDS is stopped.
One class of HIV drugs often used in HAART is that of the NNRTIs, a number of which are currently on the market and several others are in various stages of development. An NNRTI currently in development is the compound 4-[[4-[[4-(2-cyano-ethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile, also referred to as TMC278. This compound not only shows pronounced activity against wild type HIV, but also against many of its mutated variants. The compound TMC278, its pharmacological activity as well as a number of procedures for its preparation have been described in WO 03/16306. Various conventional pharmaceutical dosage forms, including tablets, capsules, drops, suppositories, oral solutions and injectable solutions are exemplified therein.
Infants and children constitute a growing group of HIV infected patients. Paediatric anti-HIV medication poses particular challenges in that the dose regimens vary to a large extent due to variations in age and body weight (babies—children). Especially in the first year after birth, an infant undergoes rapid changes and body weight increases spectacularly. Because of these rapid changes at young age, dosing of a drug needs to be adjusted frequently and dosage forms need to offer flexibility in dosing. Traditional dosage forms such as pills and capsules lack the dosing flexibility required in paediatric applications. Moreover, these dosage forms are not fit for administration to young children and especially to infants in which case drinkable formulations are the preferred route of administration. These comprise liquid formulations such as syrups as well as dry formulations such as powders for reconstitution in which the drug is distributed in dry form and is converted in liquid form by adding water.
Powders for reconstitution are attractive over liquid oral dosage forms because of their compactness making them more convenient to store and transport. Incorporating TMC278 in a powder for reconstitution poses particular challenges in that it is poorly soluble in water. Upon addition of water, only a limited amount is dissolved not resulting in effective uptake of the active ingredient. Converting the free base form into an acid-addition salt can increase the solubility of this active agent, but only the salt forms with strong acids such as hydrochloric acid, show workable solubility profiles. For paediatric applications these salts are unattractive because of their low pH. Hence the challenge is to provide a powder of reconstitution using the base form of TMC278 that upon addition of water results in a dosage form that has effective therapeutic concentrations of the active.
It now has been found that the NNRTI TMC278 can be converted into a powder for reconstitution that allows a flexible application of the active ingredient and moreover is fit for paediatric applications. The powders for reconstitution of this invention may also be applied in adult patient groups that have difficulty or find inconvenience in swallowing, for example the elderly. The powders for reconstitution of this invention may contain several active ingredients thereby allowing the administration of drug cocktails in one administration. This results in a reduced number of administrations thereby being beneficial in terms of pill burden and drug compliance of the patient.